Various morphine antagonists such as naltrexone, naloxone, and nalbuphine are available by semi-synthesis from the natural opiates such as morphine, codeine, thebaine or oripavine, Scheme 1. These compounds are used extensively in medicine as antagonists (naltrexone and naloxone) and mixed agonist/antagonist (nalbuphine). Naltrexone has long been used for the treatment of alcoholism, and is the active ingredient in Vivitrol®, an extended release injectable suspension for the treatment of alcoholism and opioid dependence. Naloxone is the active ingredient in Narcan® for the reversal of opioid overdose and is used to mitigate side effects in combination with buprenorphine (Suboxone®) for the treatment of opioid addiction, with tilidine (Valoron N®) for the treatment of pain and with oxycodone (Targin®) for the prophylaxis and/or treatment of opioid-induced bowel dysfunction during the treatment of pain. Nalbuphine is the active ingredient in Nubain® and is used for the treatment of pain in very low doses particularly in women.

The introduction of the C-14 hydroxyl into various natural morphinans to produce oxycodone and oxymorphone has been reduced to practice on large scales with a high degree of efficiency by oxidation of thebaine or oripavine. Methods for direct C—H oxidation at C-14 for compounds such as codeine, morphine, or hydrocodone have been reported but are not very efficient or practical at this time. On the other hand, N-demethylation of natural opiates still represents a challenge, especially in terms of efficiency or the focus on environmentally benign procedures and reagents. Many methods have been employed for the demethylation; these include the use of cyanogen bromide (von Braun reaction),i methyl or ethyl chloroformate,ii 1-chloroethyl chloroformate (ACE-Cl),iii and microbial protocols,iv including a recently published procedure employing fungal biotransformations.v The biotransformations of several morphine alkaloids with the strain Cunninghamella echinulata and several others produced the free amines in reasonable yields and purity. Such processes, when scaled up and improved by the creation of a transgenic vector that would express the required fungal cytochrome in an E. coli carrier would have great potential as an environmentally benign N-demethylation protocol.
Recently, iron (II) as well as iron (0) catalyzed N-demethylation of several morphinan N-oxides was reported by Scammells.vi Smith et al.vii developed a method to convert N-methylated 6-oxo-14-hydroxymorphinanes to the corresponding nor compounds by treating the corresponding N-oxide with a Fe(II) based reducing agent in the presence of formic acid to form an oxazolidine. The oxazolidine can be converted to the corresponding nor-morphinane by acid hydrolysis, as shown in Scheme 2. Conversion of the N-oxide to the corresponding oxazolidine works equally well whether the 7,8 carbon bond is unsaturated or saturated, as shown with oxymorphone, Scheme 2.

The reactivity of the Burgess reagent, long associated only with the dehydration of alcohols, has been tested in a variety of ways with other functional groups. The synthesis of cis-fused sulfamidates was accomplished by the reaction of the Burgess reagent with epoxidesviii and 1,2-diols;ix and the Burgess reagent was shown to oxidize thiols to disulfides in high yields.x New applicationsxi as well as more thermally stable forms of this reagentxxi are being reported, including its chiral auxiliary version,xiii and the reagent has been used extensively in natural product syntheses.xiv 